Principal Investigator: Overstreet, Derek J. Abstract Sonoran Biosciences, Inc. SBIR PAR-14-088: Direct Phase II Prosthetic joint infections (PJIs) are especially costly, requiring two surgeries at a cost of approximately $100,000 per case to treat more than 40,000 hip and knee replacement infections each year. The near-term outlook in this area is bleak with the number of infections growing over 9% per year and few promising technologies on the horizon. At the same time, healthcare reforms are putting increasing economic pressure on hospitals tasked with managing PJIs. PJIs are caused by bacteria in biofilms which require extreme, sustained concentrations of antimicrobials to eradicate. PJIs are treated with a combination of thorough surgical removal of the infected implant and tissues (debridement) followed by local delivery of high concentrations of antimicrobials to eradicate any residual biofilm contamination. Currently, local delivery is achieved using bone cement spacers which require removal. A degradable local delivery formulation compatible with insertion of a permanent implant would enable effective PJI treatment in a single surgery, improving patient outcomes and reducing costs by about half. We have developed a new viscous controlled-release carrier, SB Gel, which is capable of providing high and sustained antimicrobial concentrations over the entire surface of a joint prosthesis and throughout a surgical site. SB Gel is the only material to combine sustained multi- day antibiotic release to eliminate contamination in the surgical site (including biofilm), compatibility on implant surfaces, and safe degradation to allow for normal healing. Preliminary studies demonstrate that SB Gel provides appropriate release rates to kill biofilm, does not hinder normal bone healing onto gel-coated implants, is safe at multiples of the human equivalent dose, and is reliably effective (20/20) in a model of one-stage treatment of deep implant infection. We now propose continuing development in a Phase II project to develop a formulation of SB Gel loaded with the antimicrobials tobramycin and vancomycin for treatment of PJI in a single surgery. Tobramycin and vancomycin have collective activity against bacteria responsible for over 95% of orthopaedic infections including PJIs. Aim 1 studies will ascertain the advantage of using two antimicrobials rather than one, evaluate bone-implant healing in a load-bearing hip replacement model, measure clearance of the SB Gel polymer after degradation, and measure in vivo delivery rates. Aim 2 will focus on optimizing the gel formulation, including evaluation of shelf life and development of a predictive model for critical quality attributes of the gel. In Aim 3, a selected formulation will be evaluated in GLP toxicity and pharmacokinetics studies in rats, a key component of the definitive testing required to proceed to clinical trials.